Mass drug administration - AbsoluteAstronomy.com

The administration of drugs to whole populations irrespective of disease status is referred to as mass drug administration (MDA). This article describes the administration of antimalarial drugs to whole populations an intervention which has been used as a malaria

Malaria

Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

-control measure for more than 70 years. Recent proposals to eliminate or even to eradicate malaria

Malaria

have led to a renewed interest in mass drug administrations in areas with very high malaria endemicity

Endemic (epidemiology)

In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...

. Drugs have been administered either directly as a full therapeutic course of treatment or indirectly through the fortification of salt. Mass drug administrations were generally unsuccessful in interrupting transmission but, in some cases, had a marked effect on parasite prevalence and on the incidence of clinical malaria. MDAs are likely to encourage the spread of drug-resistant parasites and so have only a limited role in malaria control. They may have a part to play in the management of epidemics and in the control of malaria in areas with a very short transmission season. In order to reduce the risk of spreading drug resistance, MDAs should use more than one drug and, preferably include a drug, such as an artemisinin

Artemisinin

Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...

, which has an effect on gametocytes. MDAs have low acceptance in areas with low malaria endemicity.

Background and history

Reports of attempts to control malaria through mass treatment with antimalarial drugs date back to at least 1932. In the 1950s, the WHO included mass drug administration (MDA) of antimalarial drugs as a tool for malaria eradication ‘in exceptional conditions when conventional control techniques have failed. In 1971, the WHO expert committee on malaria still recommended MDA in special circumstances. Subsequently, MDA was linked to the emergence of drug resistance

Drug resistance

Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...

and its overall benefit was questioned. Concomitantly, the goal of malaria eradication was replaced by one of prevention of malaria morbidity and mortality through the provision of effective treatment. Considering the short lasing benefit of mass drug administration one modification has been to repeat mass drug administrations which has led to the development of intermittent preventive therapy

Intermittent preventive therapy

Intermittent preventive therapy is a public health intervention aimed at treating and preventing malaria episodes in infants , children , schoolchildren and pregnant women...

Methods

Two methods of MDA, direct and indirect, have been used. In direct MDA, also referred to as ‘Mass drug treatment’, a therapeutic dose of the antimalarial drug, usually in the form of tablets, is given to an entire population. In indirect MDA, the antimalarial drug is added to food stuff, usually salt.

Direct drug administration

The first, well documented use of direct MDA took place in a rubber plantation in Liberia

Liberia

Liberia , officially the Republic of Liberia, is a country in West Africa. It is bordered by Sierra Leone on the west, Guinea on the north and Côte d'Ivoire on the east. Liberia's coastline is composed of mostly mangrove forests while the more sparsely populated inland consists of forests that open...

in 1931. Two doses of the 8-aminoquinoline

Aminoquinoline

Aminoquinoline are derivatives of quinoline, most notable for their roles as antimalarial drugs.Depending upon the location of the amino group, they can be divided into:* 4-Aminoquinoline* 8-Aminoquinoline...

plasmoquine were given weekly to workers and their families in two camps. The prevalence

Prevalence

In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

s of malaria parasite infections in humans and anopheline mosquitoes before and after treatment were studied. The authors concluded that ‘the fall in the mosquito

Mosquito

Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

infection rate of the two plasmoquine treated camps was so large as to indicate a local disappearance, or at least a great reduction, in gametocyte

Gametocyte

A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called spermatocytes, and female gametocytes are called oocytes....

carriers in the treated population’. No long-term follow up data were provided for this study or most of the trials reported subsequently. The next documented use of MDA in sub-Saharan Africa took place in 1948 and 1949 in tea estates in Kericho, Kenya

Kenya

Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...

. Ten thousand inhabitants of the tea estates received twice weekly proguanil from April to July 1948. The intervention was supplemented with DDT spraying in March and June of the following year. Before the intervention the mean malaria incidence in July, the peak of the malaria transmission season, was 56 cases per 1000 population. Following the intervention 4 malaria cases were detected in July 1949. The author therefore recommended continuation of twice weekly proguanil

Proguanil

Proguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...

prophylaxis on the estates.

The Nandi district of Kenya was the scene of a large MDA in 1953 and 1954. The target population of 83,000 received a single dose of pyrimethamine at the beginning of the malaria season in 1953 and 1954. The coverage was estimated to be around 95%. Before the intervention severe malaria epidemic

Epidemic

In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...

s had been reported in the area. Following the intervention the parasite prevalence dropped from 23% to 2.3%. The author states that in a control area parasite prevalence rose over the same period to over 50%. It was felt that the MDA was effective in curbing severe malaria epidemics. In the following three years, 1955 to 1957, pyrimethamine

Pyrimethamine

Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...

administration was replaced with Dieldrin

Dieldrin

Dieldrin is a chlorinated hydrocarbon originally produced in 1948 by J. Hyman & Co, Denver, as an insecticide. Dieldrin is closely related to aldrin, which reacts further to form dieldrin. Aldrin is not toxic to insects; it is oxidized in the insect to form dieldrin which is the active compound...

spraying to consolidate malaria control, which makes an assessment of the long term effect of this MDA impossible.

During a pilot programme in Uganda

Uganda

Uganda , officially the Republic of Uganda, is a landlocked country in East Africa. Uganda is also known as the "Pearl of Africa". It is bordered on the east by Kenya, on the north by South Sudan, on the west by the Democratic Republic of the Congo, on the southwest by Rwanda, and on the south by...

in 1959 mass administration of chloroquine

Chloroquine

Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...

/ pyrimethamine

Pyrimethamine

was combined with spraying of residual insecticides (DDT

DDT

DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....

). The success of the pilot programme led to a larger study targeted at a population of 16,000. Because of logistic problems, only half of the target population received the first round of MDA. According to the investigators, the intervention resulted in the eradication of the vector and rapid elimination of malaria from the area.

Two large trials of MDA combined with household spraying with DDT

DDT

DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....

were conducted in Cameroun

Cameroun

Cameroun was a French and British mandate territory in central Africa, now constituting the majority of the territory of the Republic of Cameroon....

and Upper Volta (Burkina Faso

Burkina Faso

Burkina Faso – also known by its short-form name Burkina – is a landlocked country in west Africa. It is surrounded by six countries: Mali to the north, Niger to the east, Benin to the southeast, Togo and Ghana to the south, and Côte d'Ivoire to the southwest.Its size is with an estimated...

) in 1960–1961. In both trials, substantial reductions in the prevalence of parasitaemia were achieved but transmission was not interrupted. In Bobo-Dioulasso

Bobo-Dioulasso

Bobo-Dioulasso is a city with a population of about 435,543 , the second largest city in Burkina Faso, Africa, after Ouagadougou, the nation's capital. The name means literally, "home of the Jula who speak Bobo," and is possibly a creation of the French who misunderstood the identity complexities...

, where primaquine

Primaquine

Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...

was used in combination with either chloroquine

Chloroquine

or amodiaquine

Amodiaquine

Amodiaquine is a 4-aminoquinoline compound related to chloroquine, used as an antimalarial and anti-inflammatory agent....

, the prevalence of gametocytes and Anopheles

Anopheles

Anopheles is a genus of mosquito. There are approximately 460 recognized species: while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus Plasmodium, which cause malaria in humans in endemic areas...

gambiae sporozoites were reduced substantially. A MDA was also combined with DDT

DDT

DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....

spraying in Zanzibar

Zanzibar

Zanzibar ,Persian: زنگبار, from suffix bār: "coast" and Zangi: "bruin" ; is a semi-autonomous part of Tanzania, in East Africa. It comprises the Zanzibar Archipelago in the Indian Ocean, off the coast of the mainland, and consists of numerous small islands and two large ones: Unguja , and Pemba...

(Dola 1974). After the MDA, the parasite prevalence in children decreased, but the overall parasite prevalence increased slightly, thus failing to deplete the reservoir

Reservoir

A reservoir , artificial lake or dam is used to store water.Reservoirs may be created in river valleys by the construction of a dam or may be built by excavation in the ground or by conventional construction techniques such as brickwork or cast concrete.The term reservoir may also be used to...

of infection.

Two trials in Northern Nigeria

Nigeria

Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...

combined multiple rounds of MDA and insecticide

Insecticide

An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...

spraying. The first trial, in Kankiya, included 11 rounds of MDA combined with 8 rounds of DDT

DDT

DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....

indoor spraying. The study was based on computer-aided models that showed that MDA could eradicate malaria in the study area if combined with an appropriate ‘insecticide attack’. Following MDAs, parasite prevalence dropped from 19% to 1%. The investigators did not consider this a success because parasite prevalence increased again after the interventions were stopped. Entomological indices also showed only a temporary reduction in transmission, which was completely reversed after the control measures ceased. Because the investigators felt that the failure of the trial to interrupt transmission was due to operational inadequacies, they recommended a much larger and more sophisticated evaluation of insecticide

Insecticide

spraying combined with MDA. This recommendation helped to launch the Garki project, also in Northern Nigeria, in 1969. In the Garki

Garki, Nigeria

Garki is a Local Government Area of Jigawa State, Nigeria. Its headquarters are in the town of Garki.It has an area of 1,408 km² and a population of 152,233 at the 2006 census.The postal code of the area is 733....

project, all 164 study villages in the catchment area were sprayed with propoxur

Propoxur

Propoxur is a carbamate insecticide and was introduced in 1959. Propoxur is a non-systemic insecticide with a fast knockdown and long residual effect used against turf, forestry, and household pests and fleas. It is also used in pest control for other domestic animals, Anopheles mosquitoes, ants,...

, a residual insecticide. In addition, in 60 villages, MDA with sulfalene

Sulfalene

Sulfalene is a sulfonamide antibacterial used for the treatment of chronic bronchitis, urinary tract infections and malaria....

/pyrimethamine

Pyrimethamine

was given at 10 week intervals for two years. In two small village clusters, house spraying was supplemented with larvicide

Larvicide

A larvicide is an insecticide that is specifically targeted against the larval life stage of an insect. Their most common use is against mosquitoes...

and MDA every two weeks. With biweekly MDA, parasite prevalence fell to 1% in the dry season and to 5% in the rainy season. MDA given every 10 weeks resulted in a parasite prevalence of 2% in the dry season and 28% in the rainy season. Transmission was not interrupted with either MDA regime. The authors concluded that spraying of residual insecticides and MDA did not result in a sustainable interruption of malaria transmission.

In 1999 in The Gambia

The Gambia

The Republic of The Gambia, commonly referred to as The Gambia, or Gambia , is a country in West Africa. Gambia is the smallest country on mainland Africa, surrounded by Senegal except for a short coastline on the Atlantic Ocean in the west....

residents living in 33 of 42 villages in the catchment area received a single dose of sulfadoxine

Sulfadoxine

Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....

/ pyrimethamine

Pyrimethamine

(SP) combined with artesunate while the residents of nine control villages received placebo. Following the MDA, 1388 children ≤10 years of age living in nine control villages and in nine matched villages which had been allocated active treatment were kept under surveillance for clinical malaria throughout the transmission season. Initially, during July and August, the mean malaria incidence rate in treated villages was significantly lower than in the control villages. In subsequent months, the incidence was slightly higher in the MDA villages. The difference between the two groups was not statistically significant. Overall no benefit of the mass drug administration was detected over the course of the malaria transmission season.

A mass drug administration campaign using S/P, artesunate

Artesunate

Artesunate is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection...

and primaquine

Primaquine

Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...

was completed in Moshi district, Tanzania

Tanzania

The United Republic of Tanzania is a country in East Africa bordered by Kenya and Uganda to the north, Rwanda, Burundi, and the Democratic Republic of the Congo to the west, and Zambia, Malawi, and Mozambique to the south. The country's eastern borders lie on the Indian Ocean.Tanzania is a state...

in 2008. The findings have yet to be published.

Outside of sub-Saharan Africa one of the larger reported malaria-control projects using MDA took place in Nicaragua in 1981 following the overthrow of the Somoza

Somoza

The Somoza family was an influential political dynasty who ruled Nicaragua as an hereditary dictatorship. Their influence exceeded their combined 43 years in the de facto presidency, as they were the power behind the other presidents of the time through their control of the National Guard...

regime. An estimated 70% of Nicaragua’s total population (1.9 million people) received chloroquine

Chloroquine

and primaquine

Primaquine

Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...

during the peak period of disease transmission (November). An estimated 9200 cases of malaria were prevented. The campaign had better results in preventing and curing malaria infections than in interrupting transmission. However, the mass administration of antimalarials was not sustainable and, as with other malaria-control efforts, collapsed following the return of politically conservative forces.

In three malaria-control projects conducted in the Indian states of Andhra Pradesh

Andhra Pradesh

Andhra Pradesh , is one of the 28 states of India, situated on the southeastern coast of India. It is India's fourth largest state by area and fifth largest by population. Its capital and largest city by population is Hyderabad.The total GDP of Andhra Pradesh is $100 billion and is ranked third...

, Uttar Pradesh

Uttar Pradesh

Uttar Pradesh abbreviation U.P. , is a state located in the northern part of India. With a population of over 200 million people, it is India's most populous state, as well as the world's most populous sub-national entity...

, and Orissa

Orissa

Orissa , officially Odisha since Nov 2011, is a state of India, located on the east coast of India, by the Bay of Bengal. It is the modern name of the ancient nation of Kalinga, which was invaded by the Maurya Emperor Ashoka in 261 BC. The modern state of Orissa was established on 1 April...

in the early 1960s, MDA had an ancillary role and was mentioned only briefly in reports on these interventions. More detailed information is available following a focal outbreak in two villages in Gujarat State during 1978-1979. Here a mass administration of chloroquine was part of a programme of intensified surveillance, case management, health education, and residual spraying. The incidence of malaria decreased so that, by the end of 1979, the authors considered the intervention to be a success. In 1980, in areas of Andhra Pradesh

Andhra Pradesh

State in India, residual spraying was combined with a MDA. During the period of lowest malaria incidence a single dose of chloroquine

Chloroquine

plus primaquine

Primaquine

Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...

was distributed to the whole population in eight villages. A second dose was given after an interval of 2–3 months. This project failed to reduce malaria incidence and was considered to be a failure.

In 1984, MDA was added to the distribution of insecticide-impregnated bed nets (ITNs) in Sabah

Sabah

Sabah is one of 13 member states of Malaysia. It is located on the northern portion of the island of Borneo. It is the second largest state in the country after Sarawak, which it borders on its southwest. It also shares a border with the province of East Kalimantan of Indonesia in the south...

(Malaysia), but this failed to interrupt malaria transmission. A MDA in Sumatra

Sumatra

Sumatra is an island in western Indonesia, westernmost of the Sunda Islands. It is the largest island entirely in Indonesia , and the sixth largest island in the world at 473,481 km2 with a population of 50,365,538...

, Indonesia in 1987 focused on schoolchildren. Eight months after the MDA, Plasmodium falciparum prevalence had decreased from 14% to 1%.

The only reported project with an MDA component which succeeded in permanently interrupting malaria transmission took place on the island of Aneityum, Vanuatu

Vanuatu

Vanuatu , officially the Republic of Vanuatu , is an island nation located in the South Pacific Ocean. The archipelago, which is of volcanic origin, is some east of northern Australia, northeast of New Caledonia, west of Fiji, and southeast of the Solomon Islands, near New Guinea.Vanuatu was...

. Starting in September 1991, three malaria-control activities were employed – permethrin

Permethrin

Permethrin is a common synthetic chemical, widely used as an insecticide, acaricide, and insect repellent. It belongs to the family of synthetic chemicals called pyrethroids and functions as a neurotoxin, affecting neuron membranes by prolonging sodium channel activation. It is not known to...

-impregnated bednets, larvivorous fish and the administration of three antimalarials. This MDA comprised 300 mg chloroquine

Chloroquine

base and 45 mg pyrimethamine

Pyrimethamine

weekly for nine weeks. An additional 300 mg chloroquine

Chloroquine

and 75 mg pyrimethamine

Pyrimethamine

plus 1500 mg sulfadoxine

Sulfadoxine

Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....

was added to this regimen in the first, fifth, and ninth week. Children received an adjusted equivalent of the adult dose. Follow-up consisted of yearly parasite surveillance. During the seven surveillance years following the MDA, no P.falciparum infections were detected.

MDA is included in the malaria-control policy of the People’s Republic of China

China

Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...

. Following the first malaria-control phase from 1955 to 1962, which was mostly focused on malaria surveys, mass administrations were added to vector control measures and improved case management in 10 of China’s 33 provinces. The drugs used in the administrations, mostly chloroquine and piperaquine, were provided free of charge by the central government. The economic reforms instituted by Deng Xiaoping

Deng Xiaoping

Deng Xiaoping was a Chinese politician, statesman, and diplomat. As leader of the Communist Party of China, Deng was a reformer who led China towards a market economy...

, which ultimately put an end to the provision of free health care through the central government and the emergence of resistance against the most widely used antimalarials modified the use of mass drug administrations after 1980. MDAs are now targeted at high-risk populations, specifically non-immune migratory workers who receive repeated courses during the high transmission season. According to government guidelines, piperaquine

Piperaquine

Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based...

, chloroquine

Chloroquine

, or sulfadoxine

Sulfadoxine

Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....

combined with primaquine

Primaquine

Primaquine is a medication used in the treatment of malaria and Pneumocystis pneumonia. It is a member of the 8-aminoquinoline group of drugs that includes tafenoquine and pamaquine.-Radical cure:...

can be used for mass administrations. The artemisinin derivatives are not used in mass drug administrations and are reserved for treatment failures. Malaria burden and control measures are shown in Table 1. Between 1990 and 2000 the malaria prevalence dropped from 10.6 to 1.9 / 100,000, the number of reported malaria cases dropped from 117,359 to 24,088 while the number of reported deaths attributable to malaria remained stable. These data, reported to the national government, depend on reporting from health care providers and like all data depending on passive surveillance tend to underestimate the true disease burden. However there is no reason to think that the level of underreporting has changed over the last decade. Therefore the proportional reduction in malaria disease burden is likely to be true. Malaria-control measures, including MDA, as well as major ecologic changes during the second half of the last century are likely to have been responsible for the more than 100-fold reduction in malaria burden in China since the initial surveys in 1955. The widespread use of antimalarials has been followed by the emergence of drug resistance

Drug resistance

especially in regions with high drug use. By 1995 more than 95% of P.falciparum strains isolated in the South of Yunnan

Yunnan

Yunnan is a province of the People's Republic of China, located in the far southwest of the country spanning approximately and with a population of 45.7 million . The capital of the province is Kunming. The province borders Burma, Laos, and Vietnam.Yunnan is situated in a mountainous area, with...

province were found to be resistant to chloroquine

Chloroquine

, and piperaquine

Piperaquine

while in the remainder of Yunnan

Yunnan

and Hainan

Hainan

Hainan is the smallest province of the People's Republic of China . Although the province comprises some two hundred islands scattered among three archipelagos off the southern coast, of its land mass is Hainan Island , from which the province takes its name...

province the resistance rates were 85%and 38% respectively.

Indirect MDA

A different approach to MDA consists of adding an antimalarial to an essential foodstuff, usually salt. Chloroquinized salt for malaria suppression was introduced by Pinotti in 1952 and gave promising results in a number of field trials and malaria-control programmes in Brazil.

In 1959, the WHO conducted a trial in West New Guinea (later known as Irian Jaya). Salt crystals were mixed with pyrimethamine so as to provide a 0.07% pyrimethamine salt. As there were no shops in the catchment area, each family unit received fortnightly a quantity of salt from the local teacher or another member of the village community. Within three and a half months of the onset of the campaign, clinically significant levels of pyrimethamine

Pyrimethamine

resistance were reported. It was then decided to mix the remaining stock of pyrimethaminized salt with chloroquine

Chloroquine

powder. The chloroquine base content was 0.04% or 140 mg per adult per week based on a 5g per day salt consumption. The emergence of chloroquine resistance was investigated, but this was not detected. The distribution of medicated salts otherwise had no effect and it was concluded that ‘Pinotti’s method holds no prospect of malaria eradication…’. The explanation for this finding given by the author is that ‘the salt consumption by children was too small to reduce significantly the parasite reservoir of the younger age groups’.

Between 1961 and 1965, the use of chloroquinized salt was made compulsory over an area of 109,000km2 in Guyana

Guyana

Guyana , officially the Co-operative Republic of Guyana, previously the colony of British Guiana, is a sovereign state on the northern coast of South America that is culturally part of the Anglophone Caribbean. Guyana was a former colony of the Dutch and of the British...

, covering a population of 48,500 individuals. The chloroquinized salt was prepared at a state salt plant so as to provide a 0.43% chloroquine

Chloroquine

concentration. The salt was sold in two pound plastic bags. The state held the monopoly for the salt. The only alternative source was salt smuggled from Brazil. Although the chloroquinized salt was used, its popularity was limited by the occurrence of a photo-allergic dermatitis

Dermatitis

-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...

popularly called ‘salt itch’ noted in all treatment areas. Chloroquine resistance was first observed in 1962 in the area with the lowest relative uptake of chloroquinized salt. In the course of the following months, a complete replacement of the susceptible strains with resistant P. falciparum strains was observed. Following the reintroduction of DDT

DDT

DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....

spraying, the prevalence of P. falciparum declined.

In Southeast Asia, the medicated salt project at Pailin

Pailin

Pailin is a province at the northern edge of the Cardamom Mountains, in the west of Cambodia near the border of Thailand. This province is surrounded by Battambang Province, and was officially carved out of Battambang to become a separate administrative division after the surrender of the Ieng...

, on the Kampuchea-Thai

Thailand

Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...

border, demonstrated how drug resistance can develop when a large population of P. falciparum undergoing high transmission rates is exposed to intense drug pressure. The project was launched in 1960 and covered a population of approximately 20,000. Sea salt was mixed with pyrimethamine

Pyrimethamine

at a concentration of 0.05%. Between 1960 and 1961, 77 tons of medicated salt were distributed in the area. After widespread pyrimethamine resistance was reported, pyrimethamine was replaced by chloroquine

Chloroquine

. From 1961 to 1962, 75 tons of chloroquine were distributed. In two indicator districts, the parasite rates decreased from 40% to 7% and from 27% to 14%. Chloroquine resistant P.falciparum isolates were first detected in Pailin in 1962 which appeared to be widespread by 1966. However no survey was undertaken to document the prevalence in the area. The factors leading to the emergence and spread of drug resistance appear to have been the continuous introduction of non-immune migrants, attracted by the promise of quick wealth from mining of precious stones, and prolonged drug pressure resulting from individual drug consumption and mass drug administration.Unrelated to MDAs the emergence of artemisinin resistant P.falciparum strains was reported in Pailin

Pailin

in 2008, this may have been related to overuse of artemisinin derivateves including counterfeit drugs but was not related to programmatic MDAs.

Further malaria-control projects have used MDA, but have never been published, or have been published as technical reports.

Assessing effectiveness

Whether MDAs can be considered successful or not depends on the expectation of what they might achieve; many studies do not define whether their main aim was to interrupt transmission or to control disease. When MDAs were used as part of an attempt to interrupt transmission completely, they almost always failed. Only one project, conducted on Aneityum, a small isolated island in the Pacific, succeeded in permanently interrupting transmission using MDA as one of several malaria-control strategies. However, although unable to interrupt transmission, many MDA projects led to a marked reduction in parasite prevalence and probably had a marked also transient effect on malaria-related morbidity and mortality

Mortality rate

Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...

. Most of the early trials used study designs which would now be considered inadequate to provide a definitive answer on study outcome. For example, before-and-after comparisons were used frequently. Such comparisons are especially unreliable for vector-borne diseases which may show marked variations in incidence from season to season as well as from year to year. Furthermore, in several studies only a single intervention and control area or group were compared despite the fact a single control group cannot provide statistically interpretable results (see n = 1 fallacy).

The deficiencies in the study designs mentioned above reflect the evolution of research methodology over the last 50 years. The evaluation of an intervention such as MDA is complicated by the fact that the effect of the intervention on transmission can only be measured at the community and not at the individual level. Trial methods which use a community, a village, or a cluster as unit of inference have taken longer to evolve than those used for individually randomized trials. There are, with some notable exceptions, few properly designed and analysed cluster randomized trials conducted by health care researchers prior to 1978. One major handicap for researchers who need to use the cluster approach, besides the need for a large sample size, is the need to use statistical methods that differ from the familiar methods used in individually randomized trials. Significant progress has been made in the development of statistical methods for the analysis of correlated data

Correlation

In statistics, dependence refers to any statistical relationship between two random variables or two sets of data. Correlation refers to any of a broad class of statistical relationships involving dependence....

MDA and drug resistance

The present unpopularity of MDA is not only due to doubts regarding the health benefit of this intervention but to the fear that MDAs will facilitate the spread of drug resistance

Drug resistance

. Concern that MDA would cause pyrimethamine

Pyrimethamine

and later chloroquine

Chloroquine

resistance was first raised in the early 1960s. Circumstantial evidence linked the use of medicated salts to the emergence of chloroquine resistance in the 1980s: Chloroquine resistance emerged first in three foci, namely South America

South America

South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...

(Colombia

Colombia

Colombia, officially the Republic of Colombia , is a unitary constitutional republic comprising thirty-two departments. The country is located in northwestern South America, bordered to the east by Venezuela and Brazil; to the south by Ecuador and Peru; to the north by the Caribbean Sea; to the...

, Venezuela

Venezuela

Venezuela , officially called the Bolivarian Republic of Venezuela , is a tropical country on the northern coast of South America. It borders Colombia to the west, Guyana to the east, and Brazil to the south...

, Brazil

Brazil

Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...

), Southeast Asia

Southeast Asia

Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...

(Thailand

Thailand

/Kampuchea), and Africa

Africa

Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...

(Tanzania

Tanzania

/Kenya

Kenya

Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...

). Payne has argued that the one common factor between these three epidemiologically diverse areas was widespread distribution of medicated salts prior to the emergence of chloroquine resistance.

In contrast to indirect MDA, emergence of drug resistance has not been linked to the administration of therapeutic doses of antimalarials through direct MDA programmes. The likely explanation lies in the different pharmacokinetic profiles that result from these two methods of drug administration. The administration of therapeutically dosed antimalarial drugs results in a single peak drug level which kills all susceptible strains. Only during the terminal half life of the drug when the concentration drops below the C_min, the inhibitory concentration which kills the large majority of a parasite population, will new infections with more resistant strains have a survival advantage. Thus drugs with a very short terminal half life, including artemisinin derivatives, carry a lower risk of selecting resistant parasites than longer acting drugs. In contrast, the administration of medicated salts is likely to result in drug levels undulating in the sub-lethal range, which reach a steady state

Steady state

A system in a steady state has numerous properties that are unchanging in time. This implies that for any property p of the system, the partial derivative with respect to time is zero:...

after several doses have been administered. The situation is worse if drugs such as chloroquine

Chloroquine

are used which accumulate progressively. This situation, a steady increase in drug concentration, is identical to the experimental design used for the in vitro induction of drug resistance. Medicated salt projects can be considered as large scale in vivo experiments designed to select resistant parasites.

MDA and drug toxicity

The administration of antimalarials to large numbers of individuals with little or no preliminary screening could result in significant toxicity

Toxicity

Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

as nearly all antimalarials in common use can occasionally cause serious adverse events. For example the widespread use of 8-aminoquinolones in areas where Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...

is common carries the risk of precipitating episodes of haemolysis. Few MDA projects have reported specifically on adverse events. No life-threatening outcomes have been reported as a result of an MDA but a rare serious adverse event such as a blood dyscrasia would probably not have been detected without active surveillance for adverse events which was not reported in any of the studies. There is a theoretical risk that administration of antimalarial drugs during the course of MDAs to women in the first trimester of pregnancy, some of whom may not know that they are pregnant, could lead to foetal abnormalities. The benefit of malaria control has to be weighed against potential problems. Hence MDA is likely to be only used in areas with very high malaria endemicity.

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